phase ii study of cobimetinib in combination with vemurafenib in active melanoma brain metastases

Conditions: Active Melanoma Brain Metastases

Summary: the purpose of this study is to evaluate the effectiveness of the combination of vemurafenib with cobimetinib in patients with active melanoma brain metastases.


Eligibility criteria:
inclusion criteria: * signed informed consent * histologically confirmed metastatic melanoma (stage iv), carrying braf v600-mutation * melanoma must be documented to contain a brafv600 mutation by a clia approved laboratory * at least one measurable intracranial target lesion for which all of the following criteria are met: 1. previously untreated or progressive according to recist 1.1 (equal to or greater than 20% increase in longest diameter on baseline scan) after previous local therapy (srs and/or craniotomy) 2. immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy (srs and/or craniotomy) 3. largest diameter of ≥ 0.5cm but ≤ 4 cm as determined by contrast-enhanced mri * prior therapies for extracranial metastatic melanoma including chemo-, cytokine-, immuno-, biological- and vaccine-therapy will be allowed but prior braf or mek not allowed * ecog ps 0-2 * life expectancy \>12 weeks * age 18 years or older * adequate bone marrow function as indicated by the following: 1. anc \> 1500/µl 2. platelets ≥ 100,000/µl 3. hemoglobin \> 9 g/dl * adequate renal function, as indicated by creatinine =/\< 1.5 x the upper limit of normal (uln) * adequate liver function, as indicated by bilirubin =/\< 1.5 x uln * ast or alt \< 3 x uln (patients with documented liver metastases: ast and/or alt =/\< 5 x uln) * able to swallow pills * negative serum pregnancy test within 7 days prior to commencement of dosing in premenopausal women. women of non-childbearing potential may be included without serum pregnancy test if they are either surgically sterile or have been postmenopausal for ≥ 1 year * fertile men and women must use an effective method of contraception during treatment and for at least 6 months after completion of treatment as directed by their physician. effective methods of contraception are defined as those which result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly (for example implants, injectables, combined oral contraception or intra-uterine devices). at the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. (periodic abstinence \[e.g., calendar, ovulation, symptothermal, post-ovulation methods\] and withdrawal are not acceptable methods of contraception.) exclusion criteria: * active infection * prior therapy with brafi and/or meki * leptomeningeal disease * symptomatic brain metastases requiring immediate local interventions such as craniotomy or srs * increasing corticosteroid dose in 7 days prior to administration of first dose of study drug. symptomatic patients that have stable or decreasing corticosteroid use in the past 7 days will be allowed * current use of therapeutic warfarin * unresolved toxicity of national cancer institute common terminology criteria for adverse events, version 4.0 (nci v4.0) \[nci, 2009\] grade 2 or higher from previous anti-cancer therapy, except alopecia * conditions that will interfere significantly with the absorption of drugs * inability to undergo mri secondary to metal, claustrophobia, gadolinium contrast allergy * pregnant, lactating, or breast feeding women * prior radiation therapy within the last 14 days * concomitant malignancies or previous malignancies within the last 5 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix * unwillingness or inability to comply with study and follow-up procedures * the following foods/supplements are prohibited at least 7 days prior to initiation of and during study treatment: 1. st. john's wort or hyperforin 2. grapefruit juice * history of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion (rvo), or neovascular macular degeneration * uncontrolled glaucoma with intra-ocular pressures \> 21mmhg * serum cholesterol ≥ grade 2 * hypertriglyceridemia ≥ grade 2 * hyperglycemia (fasting) ≥ grade 2 * history of clinically significant cardiac dysfunction, including the following: 1. current unstable angina 2. current symptomatic congestive heart failure of nyha class 2 or higher 3. history of congenital long qt syndrome or mean qtcf \> 450 msec at baseline or uncorrectable electrolyte abnormalities 4. uncontrolled hypertension ≥ grade 2 (patients with a history hypertension controlled with anti-hypertensives to ≤ grade 1 are eligible) 5. left ventricular ejection fraction (lvef) below 50% 6. uncontrolled arrhythmias 7. myocardial infarction, severe/unstable angina, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack within the previous 6 months